Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans

Abstract

Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4 variants. Through fine-mapping, we identified markers in four regions that better capture the association with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13). We also identified statistically significant associations with markers in four separate regions (8q24, 10q22, 11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants. In aggregate, the more informative markers found in the study enhance the association of these risk regions with breast cancer in African Americans [per allele odds ratio (OR) = 1.18, P = 2.8 × 10(-24) versus OR = 1.04, P = 6.1 × 10(-5)]. In this detailed analysis of the known breast cancer risk loci, we have validated and improved upon markers of risk that better characterize their association with breast cancer in women of African ancestry.

Figure 1.

RAFs in Europeans and African Americans. The distribution of RAFs for the 19 index SNPs (from Table 1) in HapMap CEU (CHB for rs2046210) and African Americans (AA). The variants are sorted based on the RAF in the GWAS population.

Figure 2.

–Log P plots for common alleles at eight breast cancer risk loci in African Americans. –Log P-values for risk-associated alleles in African Americans from logistic regression models adjusted for age, study, global ancestry (the first 10 eigenvectors) and local ancestry. P-values are for overall breast cancer risk except for 8q24, which is for ER+ breast cancer. Pairwise correlations (r²) in the HapMap CEU population are shown in relation to markers identified through fine-mapping in African Americans (diamond), except for 11q13, where r² is shown in HapMap YRI as the marker is monomorphic in CEU. Squares denote genotyped SNPs; circles, imputed SNPs. Gray squares and circles denote that r² cannot be estimated (not in HapMap or monomorphic in CEU). Red arrows denote markers identified in African Americans; yellow arrows, GWAS index variants. Each panel shows a –log P plot for common alleles for regions: (A) 2q35; (B) 5q11; (C) 8q24; (D) 10q22; (E)10q26; (F) 11q13; (G) 16q12; (H) 19p13. The plots were generated using LocusZoom (55).